Stem and progenitor cells derived from the bone marrow may play a role in ongoing endothelial repair (Kalka et al., 2000). Impaired mobilization or depletion of these cells may contribute to endothelial dysfunction and cardiovascular disease progression. Indeed, in healthy men, levels of circulating progenitor cells may be a surrogate biologic marker for vascular function and cumulative cardiovascular risk. Recent advances in basic science have also established a fundamental role for endothelial stem and progenitor cells in postnatal neovascularization and cardiac regeneration. Improvement of neovascularization after critical ischemia is an important therapeutic option after myocardial infarction or limb ischemia. Until recently, neovascularization of ischemic tissue in the adult was believed to be restricted to migration and proliferation of mature endothelial cells, a process termed “angiogenesis”. Meanwhile, increasing evidence suggests that circulating stem and progenitor cells home to sites of ischemia and contribute to the formation of new blood vessels. In analogy to the embryonic development of blood vessels from primitive endothelial progenitors (angioblasts), this process is referred to as “vasculogenesis”. The importance of circulating stem and progenitor cells is demonstrated by the fact that genetic inhibition of their recruitment inhibits tumor angiogenesis. Stem and progenitor cells can be mobilized from the bone marrow into the circulation by vascular endothelial growth factor (“VEGF”) or stromal cell-derived factor (“SDF-1”). Both VEGF and SDF-1 are profoundly up-regulated in hypoxic tissue suggesting that VEGF and SDF-1 may constitute homing signals to recruit circulating stem and progenitor cells to enhance endogenous repair mechanisms after critical ischemia.
The present inventors have recently shown that infusion of bone marrow mononuclear cells derived from patients with ischemic heart disease is significantly less effective in improving perfusion of ischemic tissue in a hind limb ischemia animal model. Moreover, bone marrow cells of patients with ischemic heart disease reveal a reduced colony forming activity and an impairment of migratory response towards VEGF and SDF-1, which are potent chemoattractive and mobilizing agents (Heeschen C et al., Circulation 2004; 109(13): 1615-22.) Moreover, the present inventors were also able to demonstrate that in experimental models of tissue ischemia, recruitment of systemically infused stem/progenitor cells is significantly lower as compared to the recruitment of stem/progenitor cells derived from healthy donors. While in patients with acute coronary syndromes, the present inventors have observed a marked increase in systemic VEGF levels within 10 hours after onset of symptoms (Heeschen et al. Circulation 2003; 107(4):524-30), in another set of patients with acute myocardial infarctions, systemic VEGF levels three days after the acute event had already decreased and did not significantly differ from levels measured in patients without coronary heart disease (Lee et al. NEJM 2000; 342:626-33). Taken together, these data suggest that, in patients with chronic tissue damage such as old myocardial infarction, the recruitment of stem/progenitor cells will be markedly reduced due to the low expression of chemoattractant factors in the target tissue as well as due to the low functional activity of autologous stem/progenitor cells from patients with cardiovascular risk factors.
Extracorporeal shock waves (“ESW”) are generated by high voltage spark discharge under water. This causes an explosive evaporation of water, producing high energy acoustic waves. By focusing the acoustic waves with a semi-ellipsoid reflector, the waves can be transmitted to a specific tissue site (Ogden et al., 2001). ESW have been found beneficial in certain orthopedic conditions. The interactions of ESW with the targeted tissue are manifold: mechanical forces at tissue interfaces related to different acoustic impedances, as well as micro-jets of collapsing cavitation bubbles are the primary effects. However, the cellular and biochemical mechanisms, by which these physical effects may enhance healing of fractures, remain to be determined. It has been scintigraphically and sonographically implicated that local blood flow and metabolism of bone and Achilles tendon are positively affected by ESW treatment (Maier et al., 2002).
ESW therapy has shown to be effective in the treatment of orthopedic conditions including non-union of long bone fracture, calcifying tendonitis of the shoulder, lateral epicondylitis of the elbow, proximal plantar fasciitis, and Achilles tendonitis (Kruger et al., 2002). The success of shock wave therapy ranges from 80% for non-unions of long bone fractures to 15-90% for tendinopathies of the shoulder, elbow and heel. In addition, the short-term results of shock wave therapy for avascular necrosis of the femoral head appear encouraging. Shock wave therapy also showed a positive effect in promoting bone healing in animal experiments. Despite the success in clinical application, the exact mechanism of shock wave therapy remains unknown. Recent experiments in dogs demonstrated, however, that shock wave therapy enhanced neovascularization at the tendon-bone junction (Wang et al., 2002). It was hypothesized that shock wave therapy may have the potential to induce the ingrowth of new blood vessels and improvement of blood supply that lead to tissue regeneration. Indeed, a recent study in rabbits showed that shock wave therapy induces the ingrowth of neovessels and tissue proliferation associated with the early release of angiogenesis-related factors including endothelial nitric oxide synthase (eNOS) and VEGF at the tendon-bone junction in rabbits (Wang et al., 2003). Therefore, the mechanism of shock wave therapy may involve the early release of angiogenic growth factors and subsequent induction of cell proliferation and formation of neovessels at the tendon-bone junction. The occurrence of neovascularization may lead to the improvement of blood supply and play a role in tissue regeneration at the tendon-bone junction.
It was also reported that the ESW-induced VEGF-A elevation in human osteoblasts is mediated by Ras-induced superoxide and ERK-dependent HIF-1 activation.
Further, it has been demonstrated that ESW enhance osteogenic differentiation of mesenchymal stem cells in vitro as well as bone union of segmental defect in vivo through superoxide-mediated signal transduction (Wang et al., 2002a). These data indicate that the microenvironment of the defect is indeed responsive to physical ESW stimulation. Subsequent experimental studies demonstrated that mesenchymal stem cells adjacent to the segmental defect were subject to three consecutive events after ESW treatment: intensive recruitment, proliferation, and chondrogenic as well as osteogenic differentiation (Chen et al., 2004). The utilized energy for ESW treatment (0.16 mJ/mm2 EFD) did not induce side effects in rats. A major limitation of this in vivo study is that the morphological techniques utilized for the identification of mesenchymal stem cells lack specificity. Only few other studies of bone repair have monitored mesenchymal stem cells of rats, as specific markers for such cells are scarce.
Regarding the use of ESW for treating tissues other than bone, it was shown that ESW therapy ameliorates ischemia-induced myocardial dysfunction in pigs in vivo (Nishida et al., 2004).
It is noted that no prior art exists which discloses or suggests a possible link between ESW therapy and the use of stem and progenitor cells for cell therapy.
In summary, post infarction heart failure remains a major cause of morbidity and mortality in patients with coronary heart disease. Although prompt reperfusion of the occluded artery has significantly reduced early mortality rates, ventricular remodeling processes characterized by progressive expansion of the infarct area and dilation of the left ventricular cavity result in the development of heart failure in a sizeable fraction of patients surviving an acute myocardial infarction. The major goal to reverse remodeling would be the stimulation of neovascularization as well as the enhancement of regeneration of cardiac myocytes within the infarct area.
Peripheral neuropathy describes damage to the peripheral nerves. It may be caused by diseases of the nerves or as the result of systemic illnesses. Many neuropathies have well-defined causes such as diabetes, uremia, AIDS, or nutritional deficiencies. In fact, diabetes is one of the most common causes of peripheral neuropathy. Other causes include mechanical pressure such as compression or entrapment, direct trauma, fracture or dislocated bones; pressure involving the superficial nerves (ulna, radial, or peroneal); and vascular or collagen disorders such as atherosclerosis, systemic lupus erythematosus, scleroderma, and rheumatoid arthritis. Although the causes of peripheral neuropathy are diverse, they produce common symptoms including weakness, numbness, paresthesia (abnormal sensations such as burning, tickling, pricking or tingling) and pain in the arms, hands, legs and/or feet. A large number of cases are of unknown cause.
Therapy for peripheral neuropathy differs depending on the cause. For example, therapy for peripheral neuropathy caused by diabetes involves control of the diabetes. In entrapment or compression neuropathy, treatment may consist of splinting or surgical decompression of the ulnar or median nerves. Peroneal and radial compression neuropathies may require avoidance of pressure. Physical therapy and/or splints may be useful in preventing contractures (a condition in which shortened muscles around joints cause abnormal and sometimes painful positioning of the joints).
Ischemic peripheral neuropathy is a frequent, irreversible complication of lower extremity vascular insufficiency. It has been shown that ischemic peripheral neuropathy can be prevented and/or reversed by gene transfer of an endothelial cell mitogen (e.g. VEGF) designed to promote therapeutic angiogenesis (Schratzberger P, et al.). The major goal to reverse vascular insufficiency would thus be the stimulation of angiogenesis and the regeneration of the vascular tissue within the area affect by peripheral neuropathy.
The technical problem underlying the present invention in thus to enhance the cell therapy and regeneration of tissues affected by a cardiovascular or a neurological disease.
According to the invention, this problem is solved by the provision of a method for improving cell therapy in a patient suffering from a cardiovascular disease or a neurological disease comprising a treatment by means of shock waves of an tissue of the patient affected by the disease, which tissue is targeted for cell therapy.